Methods for the treatment of diseases using malonyl-coa decarbox ylase inhibitors

ABSTRACT

The present invention relates to methods for the prophylaxis, management and treatment of certain diseases modulated by the inhibition of the enzyme malonyl-coenzyme A decarboxylase (malonyl-CoA decarboxylase, MCD) by the administration of a composition containing as an active ingredient a compound according to Formula I. In particular, the invention relates to methods for the prophylaxis, management and treatment of cardiovascular diseases, diabetes, acidosis, cancers, and obesity through the administration of a compound which inhibits malonyl-coenzyme A decarboxylase activity. The present invention also includes within its scope the novel process for the preparation of certain compounds.

[0001] This application claims the benefits of provisional applicationsserial No. 60/265380 and No. 60/264552 filed on Jan. 26, 2000. Theentire disclosure is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to methods for the prophylaxis,management and treatment of certain diseases modulated by the inhibitionof the enzyme malonyl-coenzyme A decarboxylase (malonyl-CoAdecarboxylase, MCD) by the administration of a composition containing asan active ingredient a compound according to Formula I. In particular,the invention relates to methods for the prophylaxis, management andtreatment of cardiovascular diseases, diabetes, acidosis, cancers, andobesity through the administration of a compound which inhibitsmalonyl-coenzyme A decarboxylase activity. The present invention alsoincludes within its scope the novel process for the preparation ofcertain compounds.

BACKGROUND

[0003] Malonyl-CoA is an important metabolic intermediary produced bythe enzyme Acetyl CoA Carboxylase (ACC) in the body. In the liver,adipocytes, and other tissues, malonyl-CoA is a substrate for fatty acidsynthase (FAS). ACC and malonyl-CoA are found in skeletal muscle andcardiac muscle tissue, where fatty acid synthase levels are low. Theenzyme malonyl-CoA decarboxylase (MCD, EC 4.1.1.9) catalyzes theconversion of malonyl-CoA to acetyl-CoA and thereby regulatesmalonyl-CoA levels. MCD activity has been described in a wide array oforganisms, including prokaryotes, birds, and mammals. It has beenpurified from the bacteria Rhizobium trifolii (An et al., J. Biochem.Mol. Biol. 32:414-418(1999)), the uropygial glands of waterfowl(Buckner, et al., Arch. Biochem. Biophys 177:539(1976); Kim andKolattukudy Arch. Biochem. Biophys 190:585(1978)), rat livermitochondria (Kim and Kolattukudy, Arch. Biochem. Biophys.190:234(1978)), rat mammary glands (Kim and Kolattukudy, Biochim.Biophys, Acta 531:187(1978)), rat pancreatic β-cell (Voilley et al.,Biochem. J. 340:213 (1999)) and goose (Anser anser) (Jang et al., J.Biol. Chem. 264:3500 (1989)). Identification of patients with MCDdeficiency led to the cloning of a human gene homologous to goose andrat MCD genes (Gao et al., J. Lipid. Res. 40:178 (1999); Sacksteder etal., J. Biol. Chem. 274:24461(1999); FitzPatrick et al., Am. J. Hum.Genet. 65:318(1999)). A single human MCD mRNA is observed by NorthernBlot analysis. The highest mRNA expression levels are found in muscleand heart tissues, followed by liver, kidney and pancreas, withdetectable amounts in all other tissues examined.

[0004] Malonyl-CoA is a potent endogenous inhibitor of carnitinepalmitoyltransferase-I (CPT-I), an enzyme essential for the metabolismof long-chain fatty acids. CPT-I is the rate-limiting enzyme in fattyacid oxidation and catalyzes the formation of acyl-carnitine, which istransported from the cytosol across the mitochondrial membranes by acylcarnitine translocase. Inside of the mitochondria the long-chain fattyacids are transferred back to CoA form by a complementary enzyme,CPT-II, and, in the mitochondria, acyl-CoA enters the β-oxidationpathway generating acetyl-CoA. In the liver, high levels of acetyl-CoAoccur for example following a meal, leading to elevated malonyl-CoAlevels, which inhibit CPT-I, thereby preventing fat metabolism andfavoring fat synthesis. Conversely, low malonyl-CoA levels favor fattyacid metabolism by allowing the transport of long-chain fatty acids intothe mitochondria. Hence, malonyl-CoA is a central metabolite that playsa key role in balancing fatty acid synthesis and fatty acid oxidation(Zammit, Biochem. J. 343:5050-515(1999)). Recent work indicates that MCDis able to regulate cytoplasmic as well as mitochondrial malonyl-CoAlevels [Alam and Saggerson, Biochem J. 334:233-241(1998); Dyck et al.,Am J Physiology 275: H2122-2129(1998)].

[0005] Although malonyl-CoA is present in muscle and cardiac tissues,only low levels of FAS have been detected in these tissues. It isbelieved that the role of malonyl-CoA and MCD in these tissues is toregulate fatty acid metabolism. This is achieved via malonyl-CoAinhibition of muscle (M) and liver (L) isoforms of CPT-I, which areencoded by distinct genes (McGarry and Brown, Eur. J. Biochem.244:1-14(1997)). The muscle isoform is more sensitive to malonyl-CoAinhibition (IC50 0.03 μM) than the liver isoform (IC₅₀ 2.5 μM).Malonyl-CoA regulation of CPT-I has been described in the liver, heart,skeletal muscle and pancreatic β-cells. In addition, malonyl-CoAsensitive acyl-CoA transferase activity present in microsomes, perhapspart of a system that delivers acyl groups into the endoplasmicreticulum, has also been described (Fraser et al., FEBS Lett. 446: 69-74(1999)).

[0006] Cardiovascular Diseases: The healthy human heart utilizesavailable metabolic substrates. When blood glucose levels are high,uptake and metabolism of glucose provide the major source of fuel forthe heart. In the fasting state, lipids are provided by adipose tissues,and fatty acid uptake and metabolism in the heart down regulate glucosemetabolism. The regulation of intermediary metabolism by serum levels offatty acid and glucose comprises the glucose-fatty acid cycle (Randle etal., Lancet, 1:785-789(1963)). Under ischemic conditions, limited oxygensupply reduces both fatty acid and glucose oxidation and reduces theamount of ATP produced by oxidative phosphorylation in the cardiactissues. In the absence of sufficient oxygen, glycolysis increases in anattempt to maintain ATP levels and a buildup of lactate and a drop inintracellular pH results. Energy is spent maintaining ion homeostasis,and myocyte cell death occurs as a result of tissue acidification,abnormally low ATP levels and disrupted cellular osmolarity.Additionally, AMPK, activated during ischemia, phosphorylates and thusinactivates ACC. Total cardiac malonyl-CoA levels drop, CPT-I activitytherefore is increased and fatty acid oxidation is favored over glucoseoxidation. The beneficial effects of metabolic modulators in cardiactissue are the increased efficiency of ATP/mole oxygen for glucose ascompared to fatty acids and more importantly the increased coupling ofglycolysis to glucose oxidation resulting in the net reduction of theproton burden in the ischemic tissue.

[0007] A number of clinical and experimental studies indicate thatshifting energy metabolism in the heart towards glucose oxidation is aneffective approach to decreasing the symptoms associated withcardiovascular diseases, such as but not limited, to myocardial ischemia(Hearse, “Metabolic approaches to ischemic heart disease and itsmanagement”, Science Press). Several clinically proven anti-angina drugsincluding perhexiline and amiodarone inhibit fatty acid oxidation viainhibition of CPT-I (Kennedy et al., Biochem. Pharmacology, 52: 273(1996)). The antianginal drugs ranolazine and trimetazidine are shown toinhibit fatty acid β-oxidation (McCormack et al., Genet. Pharmac.30:639(1998), Pepine et al., Am. J. Cardiology 84:46 (1999)).Trimetazidine has been shown to specifically inhibit the long-chain3-ketoactyl CoA thiolase, an essential step in fatty acid oxidation.(Kantor et al., Circ. Res. 86:580-588 (2000)). Dichloroacetate increasesglucose oxidation by stimulating the pyruvate dehydrogenase complex andimproves cardiac function in those patients with coronary arterydiseases (Wargovich et al., Am. J. Cardiol. 61:65-70 (1996)). InhibitingCPT-I activity through the increased malonyl-CoA levels with MCDinhibitors would result in not only a novel, but also a much safermethod, as compared to other known small molecule CPT-I inhibitors, tothe prophylaxis and treatment of cardiovascular diseases.

[0008] Most of the steps involved in glycerol-lipid synthesis occur onthe cytosolic side of liver endoplasmic reticulum (ER) membrane. Thesynthesis of triacyl glycerol (TAG) targeted for secretion inside the ERfrom diacyl gycerol (DAG) and acyl CoA is dependent upon acyl CoAtransport across the ER membrane. This transport is dependent upon amalonyl-CoA sensitive acyl-CoA transferase activity (Zammit, Biochem. J.343: 505(1999) Abo-Hashema, Biochem. 38: 15840 (1999) and Abo-Hashema,J. Biol Chem. 274:35577 (1999)). Inhibition of TAG biosynthesis by a MCDinhibitor may improve the blood lipid profile and therefore reduce therisk factor for coronary artery disease of patients.

[0009] Diabetes: Two metabolic complications most commonly associatedwith diabetes are hepatic overproduction of ketone bodies (in NIDDM) andorgan toxicity associated with sustained elevated levels of glucose.Inhibition of fatty acid oxidation can regulate blood-glucose levels andameliorate some symptoms of type II diabetes. Malonyl-CoA inhibition ofCPT-I is the most important regulatory mechanism that controls the rateof fatty acid oxidation during the onset of thehypoinsulinemic-hyperglucagonemic state. Several irreversible andreversible CPT-I inhibitors have been evaluated for their ability tocontrol blood glucose levels and they are all invariably hypoglycemic(Anderson, Current Pharmaceutical Design 4:1(1998)). A liver specificand reversible CPT-inhibitor, SDZ-CPI-975, significantly lowers glucoselevels in normal 18-hour-fasted nonhuman primates and rats withoutinducing cardiac hypertrophy (Deems et al., Am. J. Physiology 274: R524(1998)). Malonyl-CoA plays a significant role as a sensor of therelative availability of glucose and fatty acid in pancreatic β-cells,and thus links glucose metabolism to cellular energy status and insulinsecretion. It has been shown that insulin secretagogues elevatemalonyl-CoA concentration in β-cells (Prentki et al., Diabetes 45: 273(1996)). Treating diabetes directly with CPT-I inhibitors has, however,resulted in mechanism-based hepatic and myocardial toxicities. MCDinhibitors that inhibit CPT-I through the increase of its endogenousinhibitor, malonyl-CoA, are thus safer and superior as compared to CPT-Iinhibitors for treatment of diabetic diseases.

[0010] Cancers: Malonyl-CoA has been suggested to be a potentialmediator of cytotoxicity induced by fatty-acid synthase inhibition inhuman breast cancer cells and xenografts (Pizer et al., Cancer Res.60:213 (2000)). It is found that inhibition of fatty acid synthase usingantitumor antibiotic cerulenin or a synthetic analog C75 markedlyincrease the malonyl-CoA levels in breast carcinoma cells. On the otherhand, the fatty acid synthesis inhibitor, TOFA(5-(tetradecyloxy)-2-furoic acid), which only inhibits at the acetyl-CoAcarboxylase (ACC) level, does not show any antitumor activity, while atthe same time the malonyl-CoA level is decreased to 60% of the control.It is believed that the increased malonyl-CoA level is responsible forthe antitumor activity of these fatty acid synthase inhibitors.Regulating malonyl-CoA levels using MCD inhibitors thus constitutes avaluable therapeutic strategy for the treatment of cancer diseases.

[0011] Obesity: It is suggested that malonyl-CoA may play a key role inappetite signaling in the brain via the inhibition of the neuropepetideY pathway (Loftus et al., Science 288: 2379(2000)). Systemic orintracerebroventricular treatment of mice with fatty acid synthase (FAS)inhibitor cerulenin or C75 led to inhibition of feeding and dramaticweight loss. It is found that C75 inhibited expression of the prophagicsignal neuropeptide Y in the hypothalamus and acted in aleptin-independent manner that appears to be mediated by malonyl-CoA.Therefore control of malonyl-CoA levels through inhibition of MCDprovides a novel approach to the prophylaxis and treatment of obesity.

SUMMARY OF THE INVENTION

[0012] The present invention provides novel methods for the prophylaxis,management and treatment of metabolic diseases and diseases modulated byMCD inhibition by the administration of a compound according to Formula(I). In particular, these methods and pharmaceutical compositioncontaining such compounds are indicated in the prophylaxis, managementand treatment of cardiovascular diseases, diabetes, acidosis, cancersand obesity.

[0013] According to the present invention, the method comprises theadministration of a compound as depicted by Formula (I):

[0014] in a pharmaceutically acceptable carrier, wherein W is as definedbelow.

[0015] According to another embodiment of the present invention, certaincompounds are prepared by a novel process, which is more fully describedbelow.

DETAILED DESCRIPTION OF THE INVENTION

[0016] The detailed description of the invention that follows is notintended to be exhaustive or to limit the invention to the precisedetails disclosed. It has been chosen and described to best explain thedetails of the invention to others skilled in the art.

[0017] The method of the invention relates to the administration of acompound as depicted by Formula (I):

[0018] wherein W is independently selected from:

[0019] a five or six membered aromatic ring or aromatic heterocyclicring with respective substitutents represented by the followingstructures:

[0020] wherein

[0021] R₁ is independently chosen from halo, haloalkyl, hydroxy, thiol,substituted thiol, sulfonyl, sulfinyl, nitro, cyano, amino, substitutedamino, C₁-C₆ alkyl and C₁-C₆ alkoxy, and when R₁ is hydroxy, C₁-C₆alkoxy, thiol, substituted thiol, amino, substituted amino, or C₁-C₆alkyl, such radical may be combined with R₂ or R₆ to form a ring of 5-7members when R₁ is ortho to R₂ or R₆;

[0022] R₂ is selected from alkyl, OR₃, NR₄R₅, SR₃, NR₃C(O)NR₄R₅,NR₃COR₄, NR₃CSR₄, CONR₄R₅, NR₃SO₂R₄, NR₃SO₂NR₄R₅, a five membered ringwith the following structures:

[0023] or may be combined with R₁ to form a ring of 5-7 members when R₂is ortho to R₁;

[0024] R₃ is hydrogen, alkyl, aryl, heterocyclyl, or may form a ring of5-7 members with R₄ or R₅;

[0025] R₄ is hydrogen, alkyl, aryl, heterocyclyl, or may form a ring of5-7 members with R₅ or R₃;

[0026] R₅ is hydrogen, alkyl, aryl, or heterocyclyl, or may form a ringof 5-7 members with R₃ or R₄;

[0027] R₆ is selected from alkyl, OR₃, NR₄R₅, SR₃, NR₃C(O)NR₄R₅,NR₃COR₄, NR₃CSR₄, CONR₄R₅, NR₃SO₂R4, NR₃SO₂NR₄R₅, or may be combinedwith R₁ to form a ring of 5-7 members when R₆ is ortho to R₁;

[0028] R₇, R₈, R₉, and R₁₀ may be equal or different and are selectedfrom hydrogen, alkyl, aryl, heterocyclyl, nitro, cyano, carboxylic acid,ester, amide, halo, hydroxyl, amino, substituted amino, alkoxy, acyl,ureido, sulfonamido, sulfamido, sulfonyl, sulfinyl, or guanadinyl;

[0029] R₁₁ is hydrogen, alkyl, aryl, heterocyclyl, acyl, ester,sulfonyl, ureido, or guanadinyl;

[0030] m is from zero to four;

[0031] n is from zero to two;

[0032] Z is O, S or NR₁₁;

[0033] its corresponding enantiomers, diastereoisomers or tautomers;

[0034] or a pharmaceutically acceptable salt, or a prodrug thereof in apharmaceutically-acceptable carrier.

[0035] Preferably, the method of this invention comprises theadministration of a compound as depicted by the following generalstructures in a pharmaceutically-acceptable carrier:

[0036] wherein R₁, R₂, R₆ and R₁₁ are as defined above.

[0037] More preferably, the method of this invention comprises theadministration of a compound as depicted by the following generalstructures in a pharmaceutically-acceptable carrier:

[0038] wherein R₃, R₄, and R₅ are is as defined above and Z is NR₁₁, Oor S.

[0039] Still more preferably, the method of this invention comprises thepound as depicted by the following general structures in apharmaceutically-acceptable carrier:

[0040] wherein R₇, R₈, R₉ and R₁₀ are as defined above.

[0041] In accordance with the novel process of this invention, the abovedescribed substituted imidazole derivatives are prepared according toScheme 3.

[0042] Thus, as shown in Scheme 3, imidazole derivatives are preparedfrom an amidine intermediate XI which in turn is prepared from theaniline derivatives and nitriles in the presence of a Lewis acid atelevated temperature or in the presence of a strong base such as lithiumhexamethyldisilyl amide. In the next step, the amidine is treated withan activated α-haloketone or α-haloaldehyde yielding the desiredimidazole ring system. The resulting imidazole compounds, for example,XIIIa and XIIIb, are further modified to give other derivatives such ascompounds XIV.

[0043] Definitions

[0044] As used herein, “alkyl” means a cyclic, branched, or straightchain chemical group containing only carbon and hydrogen, such asmethyl, pentyl, and adamantyl. Alkyl groups can either be unsubstitutedor substituted with one or more substituents, e.g., halogen, alkoxy,acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy,carbonyl, benzyloxy, aryl, heteroaryl, or other functionality that maybe suitably blocked, if necessary for purposes of the invention, with aprotecting group. Alkyl groups can be saturated or unsaturated (e.g.,containing —C═C— or —C≡C— subunits), at one or several positions.Typically, alkyl groups will comprise 1 to 12 carbon atoms, preferably 1to 10, and more preferably 1 to 8 carbon atoms or cyclic groupscontaining three to eight carbons.

[0045] As used herein, “lower alkyl” means a subset of alkyl, and thusis a hydrocarbon substituent, which is linear, cyclic or branched.Preferred lower alkyls are of 1 to about 6 carbons, and may be branchedor linear, and may include cyclic substituents, either as part or all oftheir structure. Examples of lower alkyl include butyl, propyl,isopropyl, ethyl, and methyl. Likewise, radicals using the terminology“lower” refer to radicals preferably with 1 to about 6 carbons in thealkyl portion of the radical.

[0046] As used herein, “amido” means a H—CON—or alkyl—CON—, aryl—CON— orheterocyclyl-CON group wherein the alkyl, aryl or heterocyclyl group isas herein described.

[0047] As used herein, “aryl” means a substituted or unsubstitutedaromatic radical having a single-ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl or anthryl), which can be optionallyunsubstituted or substituted with amino, cyano, hydroxyl, lower alkyl,haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents, andwhich may or may not include one or more heteroatoms. Preferredcarbocyclic aryl is phenyl. The term “heteroaryl” is clearlycontemplated in the term “aryl”. Preferably where the term arylrepresents a heterocycle, it is referred to as “heteroaryl”, and has oneor more heteroatom(s). Preferred are monocyclic heterocycles of 5 or 6members. Hence preferred heteroaryl is a monovalent unsaturated aromaticgroup having a single ring and having at least one hetero atom, such asN, O, or S, within the ring, which can optionally be unsubstituted orsubstituted with amino, cyano, nitro, hydroxyl, alkyl, haloalkyl,alkoxy, aryl, halo, mercapto, oxo (hence forming a carbonyl.) and othersubstituents. Examples of heteroaryl include, thienyl, pyrridyl, furyl,oxazolyl, oxadiazolyl, pyrollyl, imidazolyl, triazolyl, thiodiazolyl,pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, thiazolyl and others.

[0048] In this definition it is clearly contemplated that substitutionon the aryl ring is within the scope of this invention. Wheresubstitution occurs, the radical is called substituted aryl. Preferablyone to three, more preferably one or two, and most preferably onesubstituent occur on the aryl ring. Preferred substitution patterns infive membered rings are substituted in the 2 position relative to theconnection to the claimed molecule. Though many substituents will beuseful, preferred substituents include those commonly found in arylcompounds, such as alkyl, hydroxy, alkoxy, cyano, nitro, halo,haloalkyl, mercapto and the like.

[0049] As used herein, “amide” includes both RNR′CO— (in the case ofR=alkyl, alkaminocarbonyl—) and RCONR′— (in the case of R=alkyl, alkylcarbonylamino—).

[0050] As used herein, the term “ester” includes both ROCO— (in the caseof R=alkyl, alkoxycarbonyl—) and RCOO— (in the case of R=alkyl,alkylcarbonyloxy—).

[0051] As used herein, “acyl” means an H—CO— or alkyl—CO—, aryl—CO— orheterocyclyl—CO— group wherein the alkyl, aryl or heterocycicyl group isas herein described. Preferred acyls contain a lower alkyl. Exemplaryalkyl acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl,t-butylacetyl, butanoyl and palmitoyl.

[0052] As used herein, “halo” is a chloro, bromo, fluoro or iodo atomradical. Chloro, bromo and fluoro are preferred halides. The term “halo”also contemplates terms sometimes referred to as “halogen”, or “halide”.

[0053] As used herein, “haloalkyl” means a hydrocarbon substituent,which is linear or branched or cyclic alkyl, alkenyl or alkynylsubstituted with chloro, bromo, fluoro or iodo atom(s). Most preferredof these are fluoroalkyls, wherein one or more of the hydrogen atomshave been substituted by fluoro. Preferred haloalkyls are of 1 to about5 carbons in length, More preferred haloalkyls are 1 to about 4 carbons,and most preferred are 1 to 3 carbons in length. The skilled artisanwill recognize then that as used herein, “haloalkylene” means adiradical variant of haloalkyl, such diradicals may act as spacersbetween radicals, other atoms, or between the parent ring and anotherfunctional group. For example, the linker CHF—CHF is a haloakylenediradical.

[0054] As used herein, “heterocyclyl” means heterocyclic radicals, whichare saturated or unsaturated. These may be substituted or unsubstituted,and are attached to other via any available valence, preferably anyavailable carbon or nitrogen. More preferred heterocycles are of 5 or 6members. In six membered non-aromatic monocyclic heterocycles, theheteroatom(s) are selected from one up to three of O, N or S, andwherein when the heterocycle is five membered and non-aromatic,preferably it has one or two heteroatoms selected from O, N, or S.

[0055] As used herein, “substituted amino” means an amino radical whichis substituted by one or two alkyl, aryl, or heterocyclyl groups,wherein the alkyl, aryl or heterocyclyl are defined as above.

[0056] As used herein, “substituted thiol” means RS— group wherein R isan alkyl, an aryl, or a heterocyclyl group, wherein the alkyl, aryl orheterocyclyl are defined as above.

[0057] As used herein, “sulfonyl” means an alkylSO₂, arylSO₂ orheterocyclyl-SO₂ group wherein the alkyl, aryl or heterocyclyl aredefined as above.

[0058] As used herein, “sulfamido” means an alkyl-N—S(O)₂N—,aryl-NS(O)₂N— or heterocyclyl-NS(O)₂N— group wherein the alkyl, aryl orheterocyclcyl group is as herein described.

[0059] As used herein, “sulfonamido” means an alkyl-S(O)₂N—,aryl-S(O)₂N— or heterocyclyl- S(O)₂N— group wherein the alkyl, aryl orheterocyclcyl group is as herein described.

[0060] As used herein, “ureido” means an alkyl-NCON—, aryl-NCON— orheterocyclyl-NCON— group wherein the alkyl, aryl or heterocyclcyl groupis as herein described

[0061] As used herein, a “radical” in this specification may form a ringwith another radical as described herein. When such radicals arecombined, the skilled artisan will understand that there are nounsatisfied valences in such a case, but that specific substitutions,for example a bond for a hydrogen, is made. Hence certain radicals canbe described as forming rings together. The skilled artisan willrecognize that such rings can and are readily formed by routine chemicalreactions, and it is within the purview of the skilled artisan to bothenvision such rings and the methods of their formations. Preferred arerings having from 3-7 members, more preferably 5 or 6 members. As usedherein the term “ring” or “rings” when formed by the combination of tworadicals refers to heterocyclic or carbocyclic radicals, and suchradicals may be saturated, unsaturated, or aromatic. For example,preferred heterocyclic ring systems include heterocyclic rings, such asmorpholinyl, piperdinyl, imidazolyl, pyrrolidinyl, and pyridyl.

[0062] The skilled artisan will recognize that some structures describedherein may be resonance forms or tautomers of compounds that may befairly represented by other chemical structures, even when kinetically,the artisan recognizes that such structures are only a very smallportion of a sample of such compound(s). Such compounds are clearlycontemplated within the scope of this invention, though such resonanceforms or tautomers are not represented herein. For example,

[0063] the above substructures clearly represent the same radical andreference to either clearly contemplates the other. In addition, thefollowing compounds may represent prodrugs when R can be removed bybiological processes in situ:

[0064] Compounds and compositions herein also, specifically contemplatepharmaceutically acceptable salts, whether cationic or anionic. A“pharmaceutically-acceptable salt” is an anionic salt formed at anyacidic (e.g., carboxyl) group, or a cationic salt formed at any basic(e.g., amino) group. Many such salts are known in the art, as describedin World Patent Publication 87/05297, Johnston et al., published Sep.11, 1987 (incorporated by reference herein). Preferred counter-ions ofsalts formable at acidic groups can include cations of salts, such asthe alkali metal salts (such as sodium and potassium), and alkalineearth metal salts (such as magnesium and calcium) and organic salts.Preferred salts formable at basic sites include anions such as thehalides (such as chloride salts). Of course, the skilled artisan isaware that a great number and variation of salts may be used, andexamples exist in the literature of either organic or inorganic saltsuseful in this manner.

[0065] It is also clearly contemplated that compounds useful for themethods of this invention can be provided as biohydrolyzable prodrugs,as they are understood in the art. “Prodrug”, as used herein is anycompound wherein when it is exposed to the biological processes in anorganism, is hydrolyzed, metabolized, derivatized or the like, to yieldan active substance having the desired activity. The skilled artisanwill recognize that prodrugs may or may not have any activity asprodrugs. It is the intent that the prodrugs described herein have nodeleterious effect on the subject to be treated when dosed in safe andeffective amounts. These include for example, biohydrolyzable amides andesters. A “biohydrolyzable amide” is an amide compound which does notessentially interfere with the activity of the compound, or that isreadily converted in vivo by a cell, tissue, or human, mammal, or animalsubject to yield an active compound of the invention. A “biohydrolyzableester” refers to an ester compound of the invention that does notinterfere with the activity of these compounds or that is readilyconverted by an animal to yield an active formula (I) compound. Suchbiohydrolyzable prodrugs are understood by the skilled artisan and areembodied in regulatory guidelines.

[0066] Inasmuch as the compounds useful for this invention may containoptical centers, “optical isomer”, “stereoisomer”, “enantiomer,”“diastereomer,” as referred to herein have the standard art recognizedmeanings (cf. Hawleys Condensed Chemical Dictionary, 11th Ed.) and areincluded in the compounds claimed, whether as racemates, or theiroptical isomers, stereoisomers, enantiomers, diastereomers.

[0067] As used herein “cardiovascular diseases” include arrhthymia,atrial fibrillation, congestive heart failure, coronary artery disease,hypertension, myocardial infarction, stroke, ventricular fibrillation,among others, particularly cardiovascular ischemia such as anginapectoris and those conditions treatable by shifting metabolism withinthe cardiovascular system.

[0068] As used herein, “metabolic disease” means disorders in a mammalin which errors of metabolism, imbalances in metabolism, or sub-optimalmetabolism occur. The metabolic diseases as used herein also contemplatea disease that can be treated through the modulation of metabolism,although the disease itself may or may not be caused by specificmetabolism blockage. Particularly, such metabolic disease involvesglucose and fatty acid oxidation pathway. Still more particularly, suchmetabolic disease involves MCD or is modulated by levels of Malonyl-CoA.All these conditions are collectively referred to herein as an “MCD orMCA related disorder.”

[0069] Compositions

[0070] The compositions of the present invention comprise:

[0071] (a) a safe and therapeutically effective amount of an MCDinhibiting compound (I), prodrug or pharmaceutical salt thereof; and

[0072] (b) a pharmaceutically-acceptable carrier.

[0073] As discussed above, numerous diseases can be mediated by MCDrelated therapy. Thus, the methods of this invention are useful intherapy with regard to conditions involving this MCD activity.

[0074] Accordingly, to treat such diseases the selected compound isformulated into pharmaceutical compositions for use in prophylaxis,management and treatment of these conditions. Standard pharmaceuticalformulation techniques such as tablets, capsules and like are used.These dosage forms are prepared by known techniques, for example, thosedisclosed in Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa.

[0075] A “safe and therapeutically effective amount” of a compound usedin the present methods is an amount that is effective, to inhibit MCD atthe site(s) of activity, in a subject, a tissue, or a cell, andpreferably in an animal, more preferably in a mammal, without undueadverse side effects (such as toxicity, irritation, or allergicresponse), commensurate with a reasonable benefit/risk ratio, when usedin the manner of this invention. The specific “safe and therapeuticallyeffective amount” will, obviously, vary with such factors as theparticular condition being treated, the physical condition of thepatient, the duration of treatment, the nature of concurrent therapy (ifany), the specific dosage form to be used, the carrier employed, thesolubility of the compound therein, and the dosage regimen desired forthe composition.

[0076] The composition useful for the present invention contains theselected compound which is dispensed in a pharmaceutically-acceptablecarrier. The term “pharmaceutically-acceptable carrier”, as used herein,means one or more compatible solid or liquid filler diluents orencapsulating substances which are suitable for administration to amammal. The term “compatible”, as used herein, means that the componentsof the composition are capable of being commingled with the subjectcompound, and with each other, in a manner such that there is nointeraction which would substantially reduce the pharmaceutical efficacyof the composition under ordinary use situations.Pharmaceutically-acceptable carriers must, of course, be of sufficientlyhigh purity and sufficiently low toxicity to render them suitable foradministration preferably to an animal, preferably mammal being treated.

[0077] Some examples of substances, which can serve aspharmaceutically-acceptable carriers or components thereof, are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents;flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

[0078] The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

[0079] If the selected compound is to be injected, the preferredpharmaceutically-acceptable carrier is sterile, physiological saline,with blood-compatible suspending agent, the pH of which has beenadjusted to about 7.4. In particular, pharmaceutically-acceptablecarriers for systemic administration include sugars, starches, celluloseand its derivatives, malt, gelatin, talc, calcium sulfate, vegetableoils, synthetic oils, polyols, alginic acid, phosphate buffer solutions,emulsifiers, isotonic saline, and pyrogen-free water. Preferred carriersfor parenteral administration include propylene glycol, ethyl oleate,pyrrolidone, ethanol, and sesame oil. Preferably, thepharmaceutically-acceptable carrier, in compositions useful for thisinvention for parenteral administration, comprises at least about 90% byweight of the total composition.

[0080] The compositions useful for this invention are preferablyprovided in unit dosage form. As used herein, a “unit dosage form” is acomposition of this invention containing an amount of a compound that issuitable for administration to an animal, preferably mammal subject, ina single dose, according to good medical practice. (The preparation of asingle or unit dosage form however, does not imply that the dosage formis administered once per day or once per course of therapy. Such dosageforms are contemplated to be administered once, twice, thrice or moreper day, and are expected to be given more than once during a course oftherapy, though a single administration is not specifically excluded.The skilled artisan will recognize that the formulation does notspecifically contemplate the entire course of therapy and such decisionsare left for those skilled in the art of treatment rather thanformulation.) These compositions preferably contain from about 5 mg(milligrams), more preferably from about 10 mg to about 1000 mg, morepreferably to about 500 mg, most preferably to about 300 mg, of theselected compound.

[0081] The compositions useful for this invention may be in any of avariety of forms, suitable (for example) for oral, nasal, rectal,topical (including transdermal), ocular, intracereberally, intravenous,intramuscular, or parenteral administration. (The skilled artisan willappreciate that oral and nasal compositions comprise compositions thatare administered by inhalation, and made using available methodologies.)Depending upon the particular route of administration desired, a varietyof pharmaceutically-acceptable carriers well-known in the art may beused. These include solid or liquid fillers, diluents, hydrotropies,surface-active agents, and encapsulating substances. Optionalpharmaceutically-active materials may be included, which do notsubstantially interfere with the inhibitory activity of the compound.The amount of carrier employed in conjunction with the compound issufficient to provide a practical quantity of material foradministration per unit dose of the compound. Techniques andcompositions for making dosage forms useful in the methods of thisinvention are described in the following references, all incorporated byreference herein: Modern Pharmaceutics, Chapters 9 and 10 (Banker &Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms:Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms2d Edition (1976).

[0082] Various oral dosage forms can be used, including such solid formsas tablets, capsules, granules and bulk powders. These oral formscomprise a safe and effective amount, usually at least about 5%, andpreferably from about 25% to about 50%, of the compound. Tablets can becompressed, tablet triturates, enteric-coated, sugar-coated,film-coated, or multiple-compressed, containing suitable binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, flow-inducing agents, and melting agents. Liquid oral dosageforms include aqueous solutions, emulsions, suspensions, solutionsand/or suspensions reconstituted from non-effervescent granules, andeffervescent preparations reconstituted from effervescent granules,containing suitable solvents, preservatives, emulsifying agents,suspending agents, diluents, sweeteners, melting agents, coloring agentsand flavoring agents.

[0083] The pharmaceutically-acceptable carrier suitable for thepreparation of unit dosage forms for peroral administration arewell-known in the art. Tablets typically comprise conventionalpharmaceutically-compatible adjuvants as inert diluents, such as calciumcarbonate, sodium carbonate, mannitol, lactose and cellulose; binderssuch as starch, gelatin and sucrose; disintegrants such as starch,alginic acid and croscarmelose; lubricants such as miagnesium stearate,stearic acid and talc. Glidants such as silicon dioxide can be used toimprove flow characteristics of the powder mixture. Coloring agents,such as the FD&C dyes, can be added for appearance. Sweeteners andflavoring agents, such as aspartame, saccharin, menthol, peppermint, andfruit flavors, are useful adjuvants for chewable tablets. Capsulestypically comprise one or more solid diluents disclosed above. Theselection of carrier components depends on secondary considerations liketaste, cost, and shelf stability, which are not critical for thepurposes of the subject invention, and can be readily made by a personskilled in the art.

[0084] Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate; typicalwetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

[0085] Such compositions may also be coated by conventional methods,typically with pH or time-dependent coatings, such that the subjectcompound is released in the gastrointestinal tract in the vicinity ofthe desired topical application, or at various times to extend thedesired action. Such dosage forms typically include, but are not limitedto, one or more of cellulose acetate phthalate, polyvinylacetatephthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose,Eudragit coatings, waxes and shellac.

[0086] Compositions of the subject invention may optionally includeother drug actives.

[0087] Other compositions useful for attaining systemic delivery of thesubject compounds include sublingual, buccal and nasal dosage forms.Such compositions typically comprise one or more of soluble fillersubstances such as sucrose, sorbitol and mannitol; and binders such asacacia, microcrystalline cellulose, carboxymethyl cellulose andhydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners,colorants, antioxidants and flavoring agents disclosed above may also beincluded.

[0088] The compositions useful for this invention can also beadministered topically to a subject, e.g., by the direct application orspreading of the composition on the epidermal or epithelial tissue ofthe subject, or transdermally via a “patch”. Such compositions include,for example, lotions, creams, solutions, gels and solids. These topicalcompositions preferably comprise a safe and effective amount, usually atleast about 0.1%, and preferably from about 1% to about 5%, of thecompound. Suitable carriers for topical administration preferably remainin place on the skin as a continuous film, and resist being removed byperspiration or immersion in water. Generally, the carrier is organic innature and capable of having dispersed or dissolved therein thecompound. The carrier may include pharmaceutically-acceptable emolients,emulsifiers, thickening agents, solvents and the like.

[0089] Methods 0f Adminiatration

[0090] According to the present invention, the compounds and thecompositions thereof can be administered topically or systemically.Systemic application includes any method of introducing compound intothe tissues of the body, e.g., intra-articular, intrathecal, epidural,intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous,sublingual administration, inhalation, rectal, or oral administration.Oral administration is preferred in the present invention.

[0091] The specific dosage of the compound to be administered, as wellas the duration of treatment is to be individualised by the treatingclinicians. Typically, for a human adult (weighing approximately 70kilograms), from about 5 mg, preferably from about 10 mg to about 3000mg, more preferably to about 1000 mg, more preferably to about 300 mg,of the selected compound is administered per day. It is understood thatthese dosage ranges are by way of example only, and that dailyadministration can be adjusted depending on the factors listed above.

[0092] In all of the foregoing, of course, the selected compound can beadministered alone or as mixtures, and the compositions may furtherinclude additional drugs or excipients as appropriate for theindication. For example, in the treatment of cardiovascular diseases, itis clearly contemplated that the invention may be used in conjunctionwith beta-blockers, calcium antagonists, ACE inhibitors, diuretics,angiotensin receptor inhibitors, or known cardiovascular drugs ortherapies. Hence, in this example, the compositions of this inventionare useful when dosed together with another active and can be combinedin a single dosage form or composition.

[0093] The compositions can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles, and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, such as cholesterol, stearylamine, orphosphatidylcholines.

[0094] Preparation of Compounds of the Invention

[0095] The starting materials used in preparing the compounds useful forthis invention are known, made by known methods, or are commerciallyavailable. It will be apparent to the skilled artisan that methods forpreparing precursors and functionality related to the compounds claimedherein are generally described in the literature. The skilled artisangiven the literature and this disclosure is well equipped to prepare anyof the claimed compounds.

[0096] It is recognized that the skilled artisan in the art of organicchemistry can readily carry out manipulations without further direction,that is, it is well within the scope and practice of the skilled artisanto carry out these manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification and saponification and the like. Thesemanipulations are discussed in standard texts such as March AdvancedOrganic Chemistry (Wiley), Carey and Sundberg, Advanced OrganicChemistry and the like.

[0097] The skilled artisan will readily appreciate that certainreactions are best carried out when other functionality is masked orprotected in the molecule, thus avoiding any undesirable side reactionsand/or increasing the yield of the reaction. Often the skilled artisanutilizes protecting groups to accomplish such increased yields or toavoid the undesired reactions. These reactions are found in theliterature and are also well within the scope of the skilled artisan.Examples of many of these manipulations can be found for example in T.Greene and P. Wuts Protecting Groups in Organic Synthesis, 2^(nd) Ed.,John Wiley & Sons (1991).

[0098] The following example schemes are provided for the guidance ofthe reader, and represent preferred methods for making the compoundsexemplified herein. These methods are not limiting, and it will beapparent that other routes may be employed to prepare these compounds.Such methods specifically include solid phase based chemistries,including combinatorial chemistry. The skilled artisan is thoroughlyequipped to prepare these compounds by those methods given theliterature and this disclosure.

[0099] As shown in Scheme 1, aniline derivative II, which either iscommercially available or prepared easily via literature procedure, isconverted into its corresponding N-substitutedphenylhexafluoroisopropanol aniline derivatives III. The latter istransformed into the corresponding amide/carbamates (IV), urea V,sulfonamide (VI) and sulfamides (VII) according to the literatureprocedures as shown in the above scheme.

[0100] Similarly, the commercially available benzoic acid derivativeVIII is converted into its corresponding amides (IX) or esters (X) usingthe literature procedures as shown in Scheme 2.

[0101] As shown in Scheme 3, imidazole derivatives are prepared from anamidine intermediate XI which in turn is prepared from the anilinederivatives and nitriles in the presence of a Lewis acid at elevatedtemperature or in the presence of a strong base such as lithiumhexamethyldisilyl amide. In the next step, the amidine is treated withan activated α-haloketone or α-haloaldehyde to give the desiredimidazole ring system. The resulting imidazole compounds, for example,XIIIa and XIIIb, are further modified to give other derivatives such ascompounds XIV.

[0102] The aniline derivative III is converted into its correspondinghydrazine XV, which is reacted with diketones to give the substitutedpyrazoles XVI in good yield. Alternatively, the reaction of thehydrazine XV with β-cyanoketone results in 5-aminopyrazoles XVII, whichis then converted to give the pyrazole derivatives XVI.

[0103] Biological Activity

[0104] In Vitro MCD Inhibitory Assay:

[0105] A spectrophotometric method for the determination of malonyl-CoAdecarboxylase activity assay described in the literature, is adapted andmodified for MCD inhibitory activity assay in a high-throughput format(Kolattukudy et al., Methods in Enzymology 71:150(1981)). The followingreagents are added into a 96 well titer plate: Tris-HCI buffer, 20 μL;DTE, 10 μL; I-malate, 20 μL; NAD, 10 μL; NADH, 25 μL; water, 80 μL;malic dehydrogenase, 5 μL. The contents are mixed and incubated for 2min followed by the addition of 5 μL of citrate synthase. The compoundis added followed by 5 μL of malonyl-CoA decarboxylase prepared from ratheart and 20 μL of malonyl-CoA. The content is incubated and absorbenceat 460 nM is measured.

[0106] Active compounds are characterized by the concentration of thecompound that caused 50% inhibition of MCD activity (IC₅₀). Thepreferred compounds have the IC₅₀ value less than 10 μM. The mostpreferred compounds have the IC₅₀ value less than 100 nM. TABLE I IC₅₀of the MCD inhibitors Compound IC₅₀ (μM) Example 1-3 0.007 Example 2-50.604 Example 4-94 0.009 Example 4-114 0.01 Example 4-130 0.036 Example6-1 0.018 Example 6-3 0.037 Example 6-4 0.041 Example 7-1 0.067 Example8-4 0.557 Example 8-28 0.223

[0107] Glucose Oxidation and Fatty Acid Oxidation Measurement in thePerfused Rat Heart:

[0108] Isolated working hearts from male Sprague-Dawley rats aresubjected to a 60-minute aerobic perfusion period with a modifiedKrebs-Henseleit solution containing 5 mmol/L glucose; 100 μU/mL insulin;3% BAS; and 1.2 mmol/L palmitate. Working hearts are used in thesestudies to approximate the metabolic demand of the heart seen in vivo.(Kantor et al., Circulation Research 86:580-588(2000)). The testcompound is added 5 minutes into the perfusion period.

[0109] Glucose oxidation rates are determined by the quantitativecollection of ¹⁴CO₂ produced by hearts perfused with buffer containing[U14]-Glucose. Rates of fatty acid oxidation are determined by thequantitative collection of ¹⁴CO₂ produced by hearts perfused with buffercontaining [¹⁴C]palmitate (McNeill, J. H. in “Measurement ofcardiovascular function”, chapter 2, CRC press, New York (1997)).

[0110] Active compounds are characterized by an increase in glucoseoxidation as compared to control experiment (DMSO). The compounds thatcaused statistically significant increases in glucose oxidation areconsidered to be active. The preferred compounds cause statisticallysignificant increases in glucose oxidation at 20 μM. Statisticalsignificance was calculated using the Student's t test for paired orunpaired samples, as appropriate. The results with P<0.05 are consideredto be statistically significant.

EXAMPLES

[0111] To further illustrate this invention, the following examples areincluded. The examples should not, of course, be construed asspecifically limiting the invention. Variations of these examples withinthe scope of the claims are within the purview of one skilled in the artand are considered to fall within the scope of the invention asdescribed, and claimed herein. The reader will recognize that theskilled artisan, armed with the present disclosure, and skill in the artis able to prepare and use the invention without exhaustive examples.

[0112] Trademarks used herein are examples only and reflect illustrativematerials used at the time of the invention. The skilled artisan willrecognize that variations in lot, manufacturing processes, and the like,are expected. Hence the examples, and the trademarks used in them arenon-limiting, and they are not intended to be limiting, but are merelyan illustration of how a skilled artisan may choose to perform one ormore of the embodiments of the invention.

[0113]¹H nuclear magnetic resonance spectra (NMR) is measured in CDCI₃or other indicated solvents on a Varian NMR spectrometer (Unity Plus400, 400 MHz for ¹H) unless otherwise indicated and peak positions areexpressed in parts per million (ppm) downfield from tetramethylsilane.The peak multiplicities are denoted as follows, s, singlet; d, doublet;t, triplet; m, multiplet.

[0114] The following abbreviations have the indicated meanings:

[0115] Ac=acetyl

[0116] Allyl=CH₂═CH₂—CH₂—

[0117] Bn=benzyl

[0118] CDl=carbonyl diimidazole

[0119] CH₂Cl₂=dichloromethane

[0120] DIBAL=diisobutylaluminum hydride

[0121] DMAP=4-(dimethylamino)-pyridine

[0122] DMF=N,N-dimethylformamide

[0123] DMSO=dimethylsulfoxide

[0124] EDCI or EDAC=1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloric acid

[0125] ESIMS=electron spray mass spectrometry

[0126] Et₃N=triethylamine

[0127] EtOAc=ethyl acetate

[0128] HMTA=hexamethylenetetramine

[0129] Lawesson'sreagent=2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide

[0130] LDA=lithium diisopropylamide

[0131] LHMDS=lithium bis(trimethylsilyl)amide

[0132] MgSO₄=magnesium sulfate

[0133] NaHCO₃=sodium bicarbonate

[0134] Na₂CO₃=sodium carbonate

[0135] NaH=sodium hydride

[0136] NBS=N-bromosuccinimide

[0137] NCS=N-chlorosuccinimide

[0138] NH₄CI=ammonium chloride

[0139] Ph=phenyl

[0140] Py=pyridinyl

[0141] r.t.=room temperature

[0142] TFA=trifluoroacetic acid

[0143] THF=tetrahydrofuran

[0144] TLC=thin layer chromatography

[0145] TMS=trimethylsilyl

[0146] Tf₂O=triflic anhydride

[0147] Vinyl=CH₂═CH—

[0148] Alkyl group abbreviations

[0149] Me=methyl

[0150] Et=ethyl

[0151] n-Pr=normal propyl

[0152] i-Pr=isopropyl

[0153] n-Bu=normal butyl

[0154] c-Hexyl=cyclohexyl

Example 1

[0155] Preparation ofN-ethyl-2-methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-phenyl}propanamide

[0156] 2-(p-N-Ethylphenyl)-hexafluoroisopropanol (172.3 mg, 0.6 mmol)and poly(4-vinylpyridine) (204.5 mg, 1.8 mmol) are mixed in CH₂Cl₂ (3mL). Isobutyryl chloride (62.8 μL, 0.6 mmol) is added to the suspensionand the reaction mixture is stirred at room temperature for 14 hrs. Thepolymer is removed by filtration through a pad of Celite and the organicsolvent is removed under reduced pressure. The residue is purified bypreparative TLC (Hexane:EtOAc, 7:3) to afford the title compound aswhite solid (87 mg, 41%). ¹H NMR δ0.99 (d, 6H), 1.09 (t, 3H), 2.40 (m,1H), 3.71 (q, 2H), 7.37 (d, 2H), 7.84 (d, 2H); ESIMS: m/z 358 (M+H).TABLE 1 The following compounds are prepared in accordance with theprocedure described as in the above example.

Example R₄ R₃ Example 1-1 3-Indolyl-CO— —Me Example 1-2 i-Pr—(Et)₂NCH₂CH₂— Example 1-3 p-pyridinyl- HOOC(CH₂)₄— Example 1-4 i-Pr—5-Tetrazolyl-CH₂CH₂CH₂CH₂— Example 1-5 i-Pr— HOOC(CH₂)₄— Example 1-6p-CN—Ph— -nBu Example 1-7 i-Pr— CN—CH₂CH₂CH₂CH₂— Example 1-8 i-Pr— -nBuExample 1-9 Me₂(OH)C— HOOC(CH₂)₄— Example 1-10 i-Pr— MeO₂C(CH₂)₄—Example 1-11 p-pyridinyl- -nBu Example 1-12 i-Pr— -nPr Example 1-13n-Bu—CH(Et)— —Et Example 1-14 -2-Py -nBu Example 1-15 i-Pr— MeO₂CCH₂—Example 1-16 p-CN—Ph— —Et Example 1-17 i-Pr— -Allyl Example 1-18(Et)₂CH— —Et Exam le 1-19 i-Pr— —Et Example 1-20 p-pyridinyl-MeO₂C(CH₂)₄— Example 1-21 -nBu —Et Example 1-22 Me₂(OH)C— -nBu Example1-23 (Me)₂C═CH— -nPr Example 1-24 nPrCH(Me)— —Et Example 1-25c-Cyclobutanyl- —Et Example 1-26 —Et —Et Example 1-27 n-Penlyl- —EtExample 1-28 c-Pr— —Et Example 1-29 PhCH(Et)— —Et Example 1-30 -Cyclohex—Et Example 1-31 PhCH₂CH₂— -nBu Example 1-32 i-Pr—HOOC—(CH₂)₅NHCOCH(Et)— Example 1-33 Me₂(OH)C— MeO₂C(CH₂)₄— Example 1-34p-pyridinyl- —Et Example 1-35 n-Hexyl— —Et Example 1-36 i-PrCH₂CH₂— —EtExample 1-37 —Et MeO₂CCH₂— Example 1-38 PhCH₂CH₂— MeO₂CCH₂— Example 1-39EtCONHCH₂— —Et Example 1-40 i-Pr— —CH₂CH₂OH Example 1-41 -2-Py —EtExample 1-42 i-Pr— p-HOPhCH₂CH₂NHCOCH(iBu)— Example 1-43 p-pyridinyl-p-HOPhCH₂CH₂NHCOCH(iPr)— Example 1-44 (Et)₂N + CH(Me)— —Et Example 1-45PhCH₂CH₂— -Cyclohexyl Example 1-46 PhCH₂CH₂CH₂— —Et Example 1-47t-BuCH₂— —Me Example 1-48 PhCH₂CH₂— —Et Example 1-49 p-CN—Ph— —MeExample 1-50 (Et)₂NCH(Me)— —Et Example 1-51 i-Pr— —Me Example 1-52MeCH═CH— —Et Example 1-53 i-BuN(Me)CH₂— —Et Example 1-54 BnN + (Me)CH₂——Et Example 1-55 HOCH₂CH₂N(Et)CH₂— —Et Example 1-56 PhCH₂CH₂— i-Pr—Example 1-57 Me₂(OH)C— —Et Example 1-58 o-Cl—Ph— —Me Example 1-59BnN(Me)CH₂— —Et Example 1-60 i-Pr— HOOC(CH₂)₅NHCOCH(iPr)— Example 1-61o-MeOPh— —Et Example 1-62 PhCH(Et)— —Me Example 1-63 HOOCC(Me)₂CH₂— —EtExample 1-64 —Et —Me Example 1-65 o-l-Ph —Me Example 1-66 c-Pr— —MeExample 1-67 m-Me₂N—Ph— —Me Exam le 1-68 p-CN—Ph—CONHCH₂— —Et Example1-69 m-CN—Ph— —Me Example 1-70 o-CF₃—Ph— —Me Example 1-71 PhCH₂CH₂—HOOCCH₂— Example 1-72 p-pyridinyl- —Me Example 1-73 PhOCH₂CH₂CH₂— —MeExample 1-74 PhOCH(Me)— —Me Example 1-75 -Bn —Me Example 1-762-Benzopyrazinyl —Me Example 1-77 2-Naphthyl- —Me Example 1-782-Theinyl-CH₂— —Me Example 1-79 4-Py—SCH₂— —Me Example 1-80c-pentylCH₂CH₂— —Me Example 1-81 PhCH₂CH₂CH₂— —Me Example 1-82 p—EtOPh——Me Example 1-83 (Et)₂NCH₂— —Et Example 1-84 PhCH₂CH₂— -Bn Example 1-85i-Pr— HOOCCH₂— Example 1-86 MeOCH₂— —Me Example 1-87 o-Tolyl- —MeExample 1-88 (Et)₂N + CH₂— —Et Example 1-89 PhSCH₂— —Me Example 1-903,4-dimethoxyphenyl- —Me CH₂CH₂— Example 1-91 p-MeOPh— —Me Example 1-92PhCH₂OCH₂— —Me Example 1-93 o-MeOPh— —Me Example 1-94 PhCH₂CH₂— —MeExample 1-95 p-CF₃Ph— —Me Example 1-96 p-ClPhO—C(Me)₂— —Me Example 1-97—Et HOOCCH₂— Example 1-98 Ph-c(CHCH₂CH)— —Me Example 1-99 p-MeOPhCH₂CH₂——Me Example 1-100 5-Methyl-3-oxazolyl- —Me Example 1-101 PhCH═CH— —MeExample 1-102 4-Py—CH₂— —Me Example 1-103 HOOC-c(CHCH₂CH)— —Et Example1-104 -3-Py —Me Example 1-105 Biphenyl —Me Example 1-106 m-ClPh— —MeExample 1-107 2-furyl —Me Example 1-108 2-HOOC-cyclohexyl —Et Example1-109 -nPr —Me Example 1-110 3,4,5-trimethoxyphenyl —Me Example 1-111—CO₂Et —Me Example 1-112 PhCH₂CH₂CH₂CH₂— —Me Example 1-113 PhCH₂CH₂— —MeExample 1-114 i-Pr— CH₂═CHCH₂— Example 1-115 HOOCC(Me)₂CH₂CH₂— —HExample 1-116 PhOCH(Me)— —H Example 1-117 p-(n-Bu)-Ph— —Me Example 1-118PhCH₂CH₂— —Me

Example 2

[0157] Preparation of 1-diethylaminosulfonylamino-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-benzene

[0158] 2-(p-Aminophenyl)-hexafluoroisopropanol (50 mg 0.193 mmol) andDMAP (23.6 mg, 0.193 mmol) are dissolved in CH₂Cl₂ (5 mL) and addeddropwise to the sulphuryl chloride solution (130 mg, 0.965 mmol) inCH₂Cl₂ (5 mL) at −78° C. After the reaction mixture is stirred at −78°C. for 15 min, diethylamine (282 mg 3.86 mmol) solution in CH₂Cl₂ (5 mL)is introduced. The reaction mixture is stirred at −78° C. for another 1hr. The cooling bath is removed and the reaction mixture is allowed towarm to room temperature. After stirring for 1 hr, saturated aqueousNaHCO₃ is added, and the mixture is extracted with CH₂Cl₂. The combinedorganic solvent is washed with water, dilute aqueous HCI, water, andbrine. The dried (Na₂SO₄) organic solvent is removed under reducedpressure. The residue is purified by preparative TLC (CH₂Cl₂:MeOH, 10:1)and further by preparative RP-HPLC (solvent system of 40% acetonitrilein water with 0.1% TFA to 90% acetonitrile in water with 0.1% TFA over20 min) to afford the title compound as colorless solid (10.7 mg, 14%).¹H NMR δ1.03 (t, 6H), 3.26 (q, 4H), 7.19 (d, 2H), 7.61 (d, 2H); ESIMS:m/z 393 (M−H). TABLE 2 The following compounds are prepared inaccordance with the procedure described as in the above example.

Example R₄ R₅ R₃ Example 2-1 —H t-BuOCO— —H Example 2-2 —Hp-HO(CF₃)₂C—Ph— —H Example 2-3 —H -nPr —H Example 2-4 —Et —Et —H Example2-5 —(CH₂)₅— —H Example 2-6 —H -Bn —H Example 2-7 —H -Cyclohexylc-Hexyl—NHSO₂— Example 2-8 —H (Ph)₂CH— —H Example 2-9 —H4-Biphenylmethyl —H Example 2-10 —H —H —H Example 2-11 —H n-Pentyl- —HExample 2-12 —H i-PrCH₂CH₂— —H Example 2-13 —H i-PrCH₂CH₂— —Me Example2-14 -iBu -iBu —H Example 2-15 i-PrCH₂CH₂— i-PrCH₂CH₂— —H

Example 3

[0159] Preparation ofN-benzyl-N′-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea

[0160] Into a 4 mL vial is added2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (75 mg, 0.289 mmol),anhydrous pyridine (1 mL) and benzyl isocyanate (0.036 mL, 0.289 mmol).The reaction mixture was stirred at r.t. for 2 days. To the reactionmixture is added H₂O to precipitate the product. The solid is filteredand purified by preparative TLC (MeOH/CHCl₃ 10:90) to give a colorlesssolid (84.3 mg, 75%). m.p. 163-164° C. (dec). ¹H NMR (DMSO & CHCl₃) 4.23(d, 2H), 6.05 (t, 1H), 7.05 (m, 1H), 7.08 (m, 4H), 7.25 (t, 3H), 7.42(d, 2H), 8.02 (s, 1H); ESIMS: m/z 393 (M+H).

Example 4

[0161] Preparation ofN-methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carboxamide

[0162] 2-(p-N-Methylphenyl)-hexafluoroisopropanol (68 mg, 0.25 mmol) andpoly(4-vinylpyridine) (150 mg) are mixed in CH₂Cl₂ (3 mL). Morpholinylchloride (0.5 mmol) is and the reaction mixture is stirred at roomtemperature for 14 hrs. The polymer is removed by filtration through apad of Celite® and the organic solvent is removed under reducedpressure. The residue is crystallized from CH₂Cl₂ to afford the titlecompound as colorless crystal (30 mg). ¹H NMR δ3.07 (t, 4H), 3.45 (t,4H), 3.70 (s, 3H), 4.10 (s, 1H), 7.10 (d, 2H), 7.65 (d, 2H); ESMIS: m/z387 (M+H). TABLE 3 The following compounds are prepared in accordancewith the procedure described as in the above example.

Example R₄ R₅ R₃ Example 4-1 —Et Ph— —Me Example 4-2 —Me Bn- —Me Example4-3 —Me Bn- —Et Example 4-4 —H 2-F-4-Br—Ph— —Me Example 4-5 —H2,6-difluoro-Ph— —Me Example 4-6 —H 2,6-dimethoxy-Ph— —Me Example 4-7—Et Ph— —Et Example 4-8 —Me Ph— —Et Example 4-9 -Allyl Ph— —Et Example4-10 -nBu Ph— —Et Example 4-11 -Bn Ph— —Et Example 4-12 —H4-Br-2,6-dimethyl-Ph— —Me Example 4-13 CN—CH₂CH₂- Ph— —Et Example 4-14—Me PhCH₂CH₂— —Et Example 4-15 —Me p—MeO₂CPh— —Et Example 4-16—CH₂CH₂OCH₂CH₂— —Et Example 4-17 —CH₂CH₂CH(Bn)CH₂CH₂— —Et Example 4-18—Et —CH₂CH₂OH —Et Example 4-19 —Et CN—CH₂CH₂— —Et Example 4-20 —(CH₂)₅——Et Example 4-21 —(CH₂)₄— —Et Example 4-22 -nPr c-Pr-CH₂— —Et Example4-23 —Me iBu— —Et Example 4-24 -iBu lBu- —Et Example 4-25 —EtCyclohexyl- —Et Example 4-26 -iBu m- —Et NO₂PhCOOCH₂CH₂— Example 4-27—Et HO(CH₂)₄— —Et Example 4-28 —Et MeOCH₂CH₂— —Et Example 4-29 —EtMe₂NCH₂CH₂— —Et Example 4-30 4-Cl-6-Me— c-Pr—CH₂— —Et PhCH₂CH₂— Example4-31 —Et MeC(OH)(Me)CH₂— —Et Example 4-32 -Bn -2-Py —Et Example 4-33 —Me—Me —Et Example 4-34 —Me -nPr —Et Example 4-35 —Et —Et —Et Example 4-36—H 1-Piperidinyl- —Et Example 4-37 —H Ph—N(Me)— —Et Example 4-38 —Etp-HO(CF₃)₂C—Ph— —Et Example 4-39 —CH₂CH₂OH —CH₂CH₂OH —Et Example 4-40—Me —Me -nPr Example 4-41 —Me -nPr -nPr Example 4-42 —Et —Et -nPrExample 4-43 —H —NMe₂ -nPr Example 4-44 —(CH₂)₅— -nPr Example 4-45 —H1-Piperidinyl- -nPr Example 4-46 —CH₂CH₂OCH₂CH₂— -nPr Example 4-47 —EtHO(CH₂)₄— -nPr Example 4-48 —CH₂CH₂OCH₂CH₂— —CH₂CH₂OH Example 4-49—CH₂CH₂OH HOCH₂CH₂CH₂— -nPr Example 4-50 —CH₂CH₂OH 1-Morpholinyl- -nPrCH₂CH₂— Example 4-51 EtO₂CCH₂— EtO₂CCH₂— -nPr Example 4-52 —Et —CH₂CONH₂-nPr Example 4-53 CN—CH₂CH₂— 1-Morpholinyl- -nPr CH₂CH₂CH₂— Example 4-54Me₂NCH₂CH₂CH₂— Me₂NCH₂CH₂CH₂— -nPr Example 4-55 —CH₂CH₂OCH₂CH₂— —HExample 4-56 —CH₂CH₂OCH₂CH₂— n-Pentyl- Example 4-57 —CH₂CH₂OCH₂CH₂—n-Hexyl— Example 4-58 —CH₂CH₂OCH₂CH₂— n-Haptyl— Example 4-59Me₂N(+)CH₂CH₂CH₂— -nPr Example 4-60 —Et HO(CH₂)₄— -nBu Example 4-61—CH₂CH₂OCH₂CH₂— -nBu Example 4-62 —CH₂CH₂OH 1-Morpholinyl- -nBu CH₂CH₂—Example 4-63 EtO₂CCH₂— EtO₂CCH₂— -nBu Example 4-64 —Et —CH₂CONH₂ -nBuExample 4-65 CN—CH₂Ch₂— 1-Morpholinyl- -nBu CH₂CH₂CH₂— Example 4-66—CH₂CH₂OCH₂CH₂— n-Octyl Example 4-67 —CH₂CH₂OCH₂CH₂— i-PrCH₂CH₂— Example4-68 —CH₂CH₂OH HOCH₂CH₂CH₂— -nBu Example 4-69 —CH₂CH₂OCH₂CH₂—c-Hexyl—CH₂CH₂— Example 4-70 —CH₂CH₂OCH₂CH₂— CN(CH₂)₃— Example 4-71—CH₂CH₂OCH₂CH₂— AcO(CH₂)₄— Example 4-72 —CH₂CH₂OCH₂CH₂— MeO₂C(CH₂)₄—Example 4-73 —CH₂CH₂OCH₂CH₂— HO(CH₂)₄— Example 4-74 —CH₂CH₂OCH₂CH₂—HOOC(CH₂)₄— Example 4-75 —Me —Me -nBu Example 4-76 —Et —Et -nBu Example4-77 —(CH₂)₄— -nBu Example 4-78 —CH₂CH₂OCH₂CH₂— EtO₂C(CH₂)₂— Example4-79 —CH₂CH₂OCH₂CH₂— PhCH₂CH₂— Example 4-80 —CH₂CH₂OH —CH₂CH₂OH -nBuExample 4-81 —Et -Cyclohex -nBu Example 4-82 —Et HO(CH₂)₄— MeO₂CCH₂—Example 4-83 HOOCCH₂— HOOCCH₂— -nBu Example 4-84 —CH₂CH₂OCH₂CH₂—MeO₂CCH₂— Example 4-85 —Et —CH₂CONH₂ MeO₂CCH₂— Example 4-86 —Me —MeMeO₂CCH₂— Example 4-87 —(CH₂)₄— MeO₂C(CH₂)₄— Example 4-88 —Et —EtMeO₂C(CH₂)₄— Example 4-89 —Et CN—CH₂CH₂— MeO₂C(CH₂)₄— Example 4-90 —EtHO(CH₂)₄— MeO₂C(CH₂)₄— Example 4-91 —Et -Cyclohex MeO₂C(CH₂)₄— Example4-92 —(CH₂)₄— HOOC(CH₂)₄— Example 4-93 —Et —Et HOOC(CH₂)₄— Example 4-94—Et CN—CH₂CH₂— HOOC(CH₂)₄— Example 4-95 —Et HO(CH₂)₄— HOOC(CH₂)₄—Example 4-96 —Et -Cyclohexyl HOOC(CH₂)₄— Example 4-97 —Et HO(CH₂)₄—EtO₂C(CH₂)₅— Example 4-98 —CH₂CH₂OCH₂CH₂— EtO₂C(CH₂)₅— Example 4-99—CH₂CH₂CH(CH₂CH₂OH)CH₂CH₂— -nBu Example 4-100 —Et HO(CH₂)₄— HOOC(CH₂)₅—Example 4-101 —CH₂CH₂OCH₂CH₂— HOOC(CH₂)₅— Example 4-102—CH₂CH₂CH(CH₂OH)CH₂CH₂— -nBu Example 4-103 —Me HO(CH₂)₆— -nBu Example4-104 —Et HO(CH₂)₄— EtO₂C(CH₂)₆— Example 4-105 -nBu HO(CH₂)₄— -nBuExample 4-106 —CH₂CH₂OCH₂CH₂— EtO₂C(CH₂)₆— Example 4-107 —Et HO(CH₂)₄—CN—(CH₂)₄— Example 4-108 —CH₂CH₂OCH₂CH₂— CN—(CH₂)₄— Example 4-109 —EtHO(CH₂)₄— HOOC(CH₂)₆— Example 4-110 —CH₂CH₂OCH₂CH₂— HOOC(CH₂)₆— Example4-111 —Et —CH₂CH₂OH -nBu Example 4-112 —CH₂CH₂OH -nPr -nBu Example 4-113—CH₂CH₂CH₂CH(CH₂OH)CH₂— -nBu Example 4-114 —CH₂CH₂OCH₂CH₂— 5-Tetrazolyl-CH₂CH₂CH₂CH₂— Example 4-115 —Me HOCH₂CH(OH)CH₂— -nBu Example 4-116—CH₂CH₂OCH₂CH₂— MeO₂CCH₂CH₂— Example 4-117 —Et HO(CH₂)₄— MeO₂CCH₂CH₂—Example 4-118 —CH₂CH₂OCH₂CH₂— MeO₂C(CH₂)₃— Example 4-119 —Et HO(CH₂)₄—MeO₂C(CH₂)₃— Example 4-120 —CH₂CH₂OCH₂CH₂— HOOCCH₂CH₂— Example 4-121—CH₂CH₂OCH₂CH₂— HO₂C(CH₂)₃— Example 4-122 —Et HO(CH₂)₄— HOOCCH₂CH₂—Example 4-123 —Et HO(CH₂)₄— HO₂C(CH₂)₃— Example 4-124 —CH₂CH₂OCH₂CH₂—4-Py—CH₂— Example 4-125 —CH₂CH₂OCH₂CH₂— P—CF3—PhCH₂— Example 4-126—CH₂CH₂OCH₂CH₂— 3-PyCH₂— Example 4-127 —CH₂CH₂OCH₂CH₂— 3-PyCH₂— Example4-128 —CH₂CH₂OCH₂CH₂— 2-Py—CH₂— Example 4-129 —CH₂CH₂OCH₂CH₂— 2-Py—CH₂—Example 4-130 —CH₂CH₂OCH₂CH₂— FCH₂CH₂CH₂— Example 4-131 —CH₂CH₂OCH₂CH₂—MeC(═CH₂)CH₂— Example 4-132 —CH₂CH₂OCH₂CH₂— 1-PyrrolylCH₂CH₂CH₂— Example4-133 —CH₂CH₂OCH₂CH₂— t-Bu— C≡CCH═CHCH₂— Example 4-134 —CH₂CH₂OCH₂CH₂—CHCCH₂— Example 4-135 —CH₂CH₂OCH₂CH₂— p-CN-Bn Example 4-136—CH₂CH₂OCH₂CH₂— MeCCCH₂— Example 4-137 —CH₂CH₂OCH₂CH₂— MeCH₂CCCH₂—Example 4-138 —CH₂CH₂OCH₂CH₂— HON═C(NH₂)— CH₂CH₂CH₂CH₂— Example 4-139—CH₂CH₂OCH₂CH₂— 3-methyl-5-(1,2,4- oxadiazolyl) (CH₂)₄—

Example 5

[0163] Preparation of2-[4-(2-pyridinylmethyl-1H-imidazol-1-yl)phenyl]-1,1,1,3,3,3hexafluoro-propan-2-ol

[0164] The title compound is obtained in a similar fashion as describedabove except 3-bromomethyl) pyridine is used instead of benzyl bromide.¹H NMR δ4.2 (s, 2H), 7.1 (m, 5H), 7.42 (d, 1H), 7.90 (d, 2H), 8.20 (s,1H), 8.35 (d, 1H); ESIMS: m/z 434 (M+H).

Example 6

[0165] Preparation of1,1,1,3,3,3-hexafluoro-2-{4-[5-(hydroxymethyl)-2-(3-methylpropyl)1H-imidazol-1-yl]phenyl}propan-2-ol

[0166] Step 1

[0167] Aluminum chloride (3g, 22.5 mmol) is added to4-(hexafluoro-2-hydroxyisopropyl)-aniline (3.89 g, 15 mmol) and2-methylbutyronitrile (15 mL) and heated at 180° C. under argonatmosphere for 14 hours. After cooling the reaction mixture to roomtemperature, EtOAc is added and subsequently washed with saturatedNaHCO₃, followed by H₂O and brine and dried over MgSO₄. EtOAc is removedunder reduced pressure and the residue is precipitated with CH₂Cl₂. Theamidine product is filtered and washed with a small amount of CH₂Cl₂ anddried under vacuum (3.49 g).

[0168] Step 2

[0169] A solution of 2-bromo-3-(-1-methylethoxy)-2-propenal (2.5g, 13.1mmol) and amidine (3 g, 8.76 mmol) obtained above in CHCl₃ and water istreated with solid potassium carbonate (1.8g, 13.1 mmol) at roomtemperature. The reaction mixture is then heated at 80° C. for 14 hoursand diluted with CH₂Cl₂. The organic layer is separated and washed withH₂O and brine and dried over MgSO₄. The crude product after removal ofsolvent is purified by silica gel column chromatography to afford theimidazole aldehyde intermediate (1.3g).

[0170] Step 3

[0171] NaBH₄ (11.2 mg, 0.296 mmol) is added to a solution of imidazolealdehyde intermediate (116.8 mg, 0.296 mmol) obtained above in MeOH. Thereaction mixture is stirred at room temperature for 4 hours. The solventis removed under reduced pressure and the residue is dissolved in EtOAc.The solution is washed with 1N HCl, saturated NaHCO₃, brine and driedover MgSO₄. The solvent is removed under reduced pressure and theresidue is purified by preparative TLC (CH₂Cl₂:MeOH, 9:1) to afford thetitle compound (56.1 mg). ¹H NMR δ0.75 (t, 3H), 1.20 (d, 3H), 1.51 (m,1H), 1.72 (m, 1H), 2.42 (m, 1H), 4.34 (q, 2H), 7.00 (s, 1H), 7.51 (d,2H), 7.95 (d, 2H); ESIMS: m/z 397 (M+H). TABLE 4 The following compoundsare prepared in accordance with the procedure described as in the aboveexamples.

Example R₇ R₈ R₉ Example 6-1 m-CN—PhCH₂SO₂— —H —H Example 6-2 i-Pr— —HCN—CH═CH— Example 6-3 i-Pr— —H EtOCOCH(Me)CH₂— Example 6-4 -sBu —HMeO₂CCH₂CH₂— Example 6-5 i-Pr— —H t-BuON═CH— Example 6-6 i-Pr— —HMeOCOCH═CH— Example 6-7 -sBu —H iPrCH(OH)— Example 6-8 i-Pr— —H MeON═CH—Example 6-9 i-Pr— —H MeO₂CCH₂CH₂— Example 6-10 m-CN—PhCH₂— —H —H Example6-11 -sBu —H nPrCH(OH)— Example 6-12 i-Pr— —H HCO— Example 6-13 -sBu —HMeOCOCH═CH— Example 6-14 i-Pr— —H MeON═CH— Example 6-15 i-Pr— —HCN—CH₂CH₂CH₂CH₂OCH₂— Example 6-16 p-pyridinyl- —H —CH₂OH Example 6-17i-Pr— —H EtOCH—C(Me)═CH— Example 6-18 i-Pr— —H 5-TetrazolylCH₂CH₂CH₂CH₂OCH₂— Example 6-19 i-Pr— —H EtON═CH— Example 6-20 -iBu —HHCO— Example 6-21 i-Pr— —H CN—CH═CH— Example 6-22 -sBu —H EtOCOCH═CH—Example 6-23 p-pyridinyl- —H HCO— Example 6-24 -sBu —H MeCH(OH)— Example6-25 i-Pr— —H HON═CH— Example 6-26 i-Pr— —H 5-tetrazolylCH₂CH₂CH₂CH₂CH₂OCH₂— Example 6-27 -sBu —H HOOCCH₂CH₂— Example 6-28 i-Pr——H CN—(CH₂)₅OCH₂— Example 6-29 p-pyridinyl- —CO₂Et —H Example 6-30 i-Pr——H EtON═CH— Example 6-31 i-Pr— —H PhON═CH— Example 6-32 i-Pr— —HHOOCCH(Me)CH₂— Example 6-33 i-Pr— —H HOOCCH₂CH₂— Example 6-34 -sBu—CH₂OH —H Example 6-35 -2-Py —H HCO— Example 6-36 i-Pr— —H —CH₂OHExample 6-37 -sBu —H HCO— Example 6-38 MeOCH₂— —H HCO— Example 6-39 -sBu—H nBuNHCH₂— Example 6-40 -sBu —CO₂Et —H Example 6-41 -sBu —H —CH₂OHExample 6-42 -sBu —H MeOCH₂CH₂NHCH₂— Example 6-43 -sBu —H iPrNHCH₂—Example 6-44 EtOCOCH₂SCH₂— —H —H Example 6-45 i-Pr— —H iBuON═CH— Example6-46 p-ClPh— —H HCO— Example 6-47 -Bn —H HCO— Example 6-48 BnS— —H —HExample 6-49 BnSO₂— —H —H Example 6-50 i-Pr— —H iBuON═CH— Example 6-51-sBu —H PhCH(OH)— Example 6-52 -sBu —H p-F—PhCH(OH)— Example 6-53 i-Pr——H nBuNHCH₂— Example 6-54 EtOCH₂CH₂S— —H —H Example 6-55m-Pyridinyl-CH₂S— —H —H Example 6-56 -sBu —H HOOC—CH═CH— Example 6-57p-pyridinyl- —CF₃ —H Example 6-58 m-MePhCH₂S— —H —H Example 6-59 -2-Py—H —CH₂OH Example 6-60 i-Pr— —H t-BuON═CH— Example 6-61 m-MeOPhCH₂S— —H—H Example 6-62 PhCH₂CH₂S— —H —H Example 6-63 2-tetrahydropyranylCH₂S——H —H Example 6-64 c-HexylS— —H —H Example 6-65 EtCH(Me)S— —H —H Example6-66 EtS— —H —H Example 6-67 i-Pr— —H PhON═CH— Example 6-68 nPrS— —H —HExample 6-69 o-MePhCH₂S— —H —H Example 6-70 iBuS— —H —H Example 6-71MeC(═CH₂)CH₂S— —H —H Example 6-72 p-NO₂PhCH₂S— —H —H Example 6-73c-HexylCH₂S— —H —H Example 6-74 (Et)₂NCH₂CH₂SO— —H —H

Example 7

[0172] Preparation ofN-phenethyl-N-methyl4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide

[0173] CDI (194.4 mg, 1.2 mmol) is added to the solution of4-(2-hydroxyhexafluoroisopropyl) benzoic acid (288 mg, 1 mmol) in THF(10 mL) at room temperature. The reaction mixture is stirred for 10minutes and N-methylphenethylamine (0.174 mL, 1.2 mmol) is introduced.The reaction mixture is then stirred for 14 hours. The solvent isremoved and the residue is dissolved in EtOAc. The organic phase iswashed with 1N HCl, saturated NaHCO₃ and brine and dried over MgSO₄. Theproduct is obtained in pure form after removal of solvents (278.8 mg).¹H NMR (CD₃OD, every peak appears as a pair) δ2.76 (t, 2H), 3.12 (s,3H), 3.44 (t, 2H), 7.01 (d, 2H), 7.20 (d, 2H), 7.30 (m, 3H), 7.62 (d,2H); ESIMS: m/z 406 (M+H). TABLE 5 The following compounds are preparedin accordance with the procedure described as in the above example

Example R₄ R₅ Example 7-1 -iBu -iBu Example 7-2 c-Pr—CH₂— -nPr Example7-3 CN—CH₂CH₂— —Et Example 7-4 MeOCH₂CH₂— —Et Example 7-5 —(CH₂)₄—Example 7-6 —(CH₂)₅— Example 7-7 -Bn —Me Example 7-8 —CH₂CH₂OH —EtExample 7-9 —CH₂CH₂OCH₂CH₂— Example 7-10 —OMe —Me Example 7-114-Bn-piperazinyl Example 7-12 PhCH₂CH₂— —Me Example 7-13 PhCH₂CH₂— —HExample 7-14 Ph—N(Me)— —H

Example 8

[0174] Preparation of5-methyl-1-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)phenyl]-1H-pyrazole-3-carboxylicacid ethyl ester.

[0175] Step 1

[0176] A solution of 4-hexafluoro-2-hydroxyisopropylaniline (10.366 g 40mmol) in 25 ml water plus 12 ml of 37% HCl at 0° C. is treated dropwisewith a solution of sodium nitrite (3.036 g 44 mmol) in 8 ml water. Afterstirring for an additional hour at 0° C., the contents are transferredto a dropping funnel and added dropwise to a vigorously stirred solutionof Tin chloride dihydrate (22.5 g 100 mmol) in 100 ml 37% HCl at 0° C.After stirring for an additional hour, the pH of the reaction mixture isadjusted to 7-8 by adding 10N sodium hydroxide with cooling in an icebath. The milky white aqueous suspension is concentrated and the residueis washed with chloroform-methanol(9:1). The combined organic extractsare dried over MgSO₄, and concentrated to obtain 5.9 g hydrazineintermediate as white solid. ¹H NMR δ4.9 (m, 2H), 7.59(d, 2H),7.82 (s,1H), 8.14 (d,2H), 9.0 (s,1H); ESIMS: m/z 275 (M+H)

[0177] Step 2

[0178] Ethyl 2,4-dioxovalerate (76.8 ul 0.547 mmol) is added to thesolution of hydrazine intermediate obtained above in 2 ml ethanol. Thereaction mixture is then heated to 80° C. for 12 hours. Then ethanol isremoved by vacuum. The reaction mixture is dissolved in EtOAc and washedwith Sat. NaHCO₃, H₂O and brine and dried over MgSO₄. Concentration andpurification by preparative TLC afford the title compound. ¹H NMR δ1.38(t, 3H), 2.38 (s, 3H), 4.39 (qt, 2H), 6.67 (s, 1H), 7.46 (d, 2H), 7.81(d, 2H); ESIMS: m/z 395 (M−H) TABLE 6 The following compounds areprepared in accordance with the procedure described as in the aboveexample.

Example R₇ R₈ R₉ Example 8-1 i-Pr— —H i-Pr— Example 8-2 —NH₂ —H Ph—Example 8-3 —NH₂ Ph— —Me Example 8-4 -2-Py —H -2-Py Example 8-5 —NH₂ Ph——CO₂Et Example 8-6 —NH₂ —Me Ph— Example 8-7 —NH₂ p-MeOPh— -Bn Example8-8 —NH₂ EtOCOCH₂CH₂— —Me Example 8-9 —NH₂ —H p-MeO₂CPh— Example 8-10—NH₂ —H -tBu Example 8-11 p-MeOPh— —H p-MeOPh— Example 8-12 —Me —Me —MeExample 8-13 —NH₂ —H -2-Thienyl Example 8-14 —Me —H EtOCOCH₂CH₂— Example8-15 EtOCOCH₂CH₂— —H —Me Example 8-16 -Bn —H —CO₂Et Example 8-17 —Me —H—Me Example 8-18 HOOCCH₂CH₂CONH— —H Ph— Example-19 —NH₂ —H p-pyridinyl-Example 8-20 —Me —H —COOH Example 8-21 —CO₂Et —H —Me Example 8-22iPrCONH— —H p-pyridinyl- Example 8-23 N-Succinyl —H p-pyridinyl- Example8-24 HOOCCH₂CH₂CONH— —H p-pyridinyl- Example 8-25 4-PyridinylCONH— —Hp-pyridinyl- Example 8-26 1-MorpholinylCONH— —H p-pyridi nyl- Example8-27 p-CN—PhCONH— —H p-pyridinyl- Example 8-28 p-pyridinyl- —H —MeExample 8-29 nPrNHCONH— —H p-pyridinyl- Example 8-30 —NH₂ —H -3-PyExample 8-31 p-ClPh—SO₂NH— —H p-pyridinyl- Example 8-32 p-l-PhSO₂NH— —Hp-pyridinyl- Example 8-33 -3-Py —H —Me Example 8-34 p-MeO-PhSO₂NH— —Hp-pyridinyl

[0179] All references described herein are hereby incorporated byreference.

[0180] Modification of the preceding embodiments is within the scope ofthe skilled artisan in formulation, given the guidance of thespecification in light of the state of the art.

[0181] While particular embodiments of this invention have beendescribed, it will be apparent to those skilled in the art that variouschanges and modifications of this invention can be made withoutdeparting from the spirit and scope of the invention. It is intended tocover, in the appended claims, all such modifications that are withinthe scope of this invention. Hence, the foregoing written specificationis considered to be sufficient to enable one skilled in the art topractice the invention. Indeed, various modifications of theabove-described makes for carrying out the invention which are obviousto those skilled in the fields of molecular biology, chemistry,medicine, pharmaceutics, or related fields are intended to be within thescope of the following claims.

We claim:
 1. A method for the inhibition of malonyl-CoA decarboxylase(MCD) in a mammal in need of such inhibition, which comprises theadministration of a therapeutically effective amount of a compositionselected from the group consisting of compounds of the followingformula:

wherein W is independently selected from: a five or six memberedaromatic ring or aromatic heterocyclic ring with respectivesubstitutents represented by the following structures:

wherein R₁ is independently chosen from halo, haloalkyl, hydroxy, thiol,substituted thiol, sulfonyl, sulfinyl, nitro, cyano, amino, substitutedamino, C₁-C₆ alkyl and C₁-C₆ alkoxy, and when R₁ is hydroxy, C₁-C₆alkoxy, thiol, substituted thiol, amino, substituted amino, or C₁-C₆alkyl, such radical may be combined with R₂ or R₆ to form a ring of 5-7members when R₁ is ortho to R₂ or R₆; R₂ is selected from alkyl, OR₃,NR₄R₅, SR₃, NR₃C(O)NR₄R₅, NR₃COR₄, NR₃CSR₄, CONR₄R₅, NR₃SO₂R₄,NR₃SO₂NR₄R₅, a five membered ring with the following structures:

 or may be combined with R₁ to form a ring of 5-7 members when R₂ isortho to R₁; R₃ is hydrogen, alkyl, aryl, heterocyclyl, or may form aring of 5-7 members with R₄ or R₅; R₄ is hydrogen, alkyl, aryl,heterocyclyl, or may form a ring of 5-7 members with R₅ or R₃; R₅ ishydrogen, alkyl, aryl, or heterocyclyl, or may form a ring of 5-7members with R₃ or R₄; R₆ is selected from alkyl, OR₃, NR₄R₅, SR₃,NR₃C(O)NR₄R₅, NR₃COR₄, NR₃CSR₄, CONR₄R₅, NR₃SO₂R4, NR₃SO₂NR₄R₅, or maybe combined with R₁ to form a ring of 5-7 members when R₆ is ortho toR₁; R₇, R₈, R₉, and R₁₀ may be equal or different and are selected fromhydrogen, alkyl, aryl, heterocyclyl, nitro, cyano, carboxylic acid,ester, amide, halo, hydroxyl, amino, substituted amino, alkoxy, acyl,ureido, sulfonamido, sulfamido, sulfonyl, sulfinyl, or guanadinyl; R₁₁is hydrogen, alkyl, aryl, heterocyclyl, acyl, ester, sulfonyl, ureido,or guanadinyl; m is from zero to four; n is from zero to two; Z is O, Sor NR₁₁; its corresponding enantiomers, diastereoisomers, or tautomers;or a pharmaceutically acceptable salt, or a prodrug thereof in apharmaceutically-acceptable carrier.
 2. A method according to claim 1comprising the administration of a composition containing compounds Ihaving the following structural formula:

wherein R₁, R₂, R₆ and R₁₁ are as defined above.
 3. A method accordingto claim 1 comprising the administration of a composition containing acompound I having the following structural formula:

wherein R₃, R₄, and R₅ are as defined above and Z is NR₁₁, O or S.
 4. Amethod according to claim 1 comprising the administration of acomposition containing compound I having the following structuralformula:

wherein R₇, R₈, R₉ and R₁₀ are as defined as above.
 5. A methodaccording to claim 3 comprising the administration of a compositioncontaining a compound selected from the group consisting of:5-((Pyridin-4-ylcarbonyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoicacid;2-Methyl-N-[4-(1H-tetraazol-5-yl)butyl]-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}propanamide;5-((2-Methylpropanoyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoicacid;N-[2-(4-Azidophenyl)-2-oxoethyl]-5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}pentanamide;N-Butyl-4-cyano-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}benzamide;N-(4-Cyanobutyl)-2-methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}propanamide;N-Butyl-2-methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}propanamide;N-Ethyl-5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}pentanamide;5-((2-Hydroxy-2-methylpropanoyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoicacid; Methyl5-((2-methylpropanoyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoate;N-Butyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}pyridine4-carboxamide;2-Methyl-N-propyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}propanamide;N,2-Diethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}hexanamide;N-Butyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}pyridine-2-carboxamide;MethylN-(2-methylpropanoyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}glycinate;4-Cyano-N-ethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}benzamide;2-Methyl-N-prop-2-enyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}propanamide;N,2-Diethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}butanamide;N-Ethyl-2-methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}propanamide;Methyl5-((pyridin-4-ylcarbonyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoate;Ethyl5-[((2-methylpropanoyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)methyl]-4,5-dihydroisoxazole-3-carboxylate;N-Ethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}pentanamide;N-Butyl-2-hydroxy-2-methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}propanamide;3-Methyl-N-propyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}but-2-enamide;N-Ethyl-2-methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}pentanamide;N-Ethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}cyclobutanecarboxamide;N-Ethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}propanamide;N-Ethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}hexanamide;N-Ethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}cyclopropanecarboxamide;N-Ethyl-2-phenyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}butanamide;N-Ethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}cyclohexanecarboxamide;N-Butyl-3-phenyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}propanamide;6-{[2-((2-Methylpropanoyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)butanoyl]amino}hexanoic acid; Methyl5-((2-hydroxy-2-methylpropanoyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoate;N-Ethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}pyridine-4-carboxamide;N-Ethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}heptanamide; N-Cyclohexyl-N,N′-diethyl-N′-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea;N,N′-Diethyl-N-(2-hydroxy-2-methylpropyl)-N′-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea;2,2-Dimethyl-N-propyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl]phenyl}hydrazinecarboxamide;N-Propyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carboxamide;N-Ethyl-N-(4-hydroxybutyl)-N′-propyl-N′-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea;N-Pentyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carboxamide;N-Hexyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carboxamide;N-Butyl-N′-ethyl-N′-(4-hydroxybutyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea;N-Butyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine4-carboxamide;N-(3-Methylbutyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine4-carboxamide;N-(3-Cyanopropyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine4-carboxamide;4-((Morpholin-4-ylcarbonyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)butyl acetate; Methyl5-((morpholin-4-ylcarbonyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoate;N-(4-Hydroxybutyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carboxamide;5-((Morpholin-4-ylcarbonyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoic acid; N-Butyl-N′,N′-dimethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea;N-Butyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}pyrrolidine-1-carboxamide;Ethyl4-((morpholin-4-ylcarbonyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)butanoate;N-(2-Phenylethyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carboxamide;N-Butyl-N′,N′-bis(2-hydroxyethyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea;N-Butyl-N′-cyclohexyl-N′-ethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea;MethylN-{[ethyl(4-hydroxybutyl)amino]carbonyl}-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}glycinate;Methyl5-((pyrrolidin-1-ylcarbonyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoate;Methyl5-({[(2-cyanoethyl)(ethyl)amino]carbonyl}{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoate;Methyl5-({[ethyl(4-hydroxybutyl)amino]carbonyl}{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoate;Methyl5-({[cyclohexyl(ethyl)amino]carbonyl}{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoate;5-((Pyrrolidin-1-ylcarbonyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)acid;5-([(Diethylamino)carbonyl]{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoicacid;5-({[(2-Cyanoethyl)(ethyl)amino]carbonyl}{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoicacid;5-({[Ethyl(4-hydroxybutyl)amino]carbonyl}{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoicacid;5-({[Cyclohexyl(ethyl)amino]carbonyl}{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoicacid; Ethyl6-({[ethyl(4-hydroxybutyl)amino]carbonyl}{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)hexanoate;Ethyl6-((morpholin-4-ylcarbonyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)hexanoate;N-Butyl-4-(2-hydroxyethyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}piperidine-1-carboxamide;6-({[Ethyl(4-hydroxybutyl)amino]carbonyl}{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)hexanoicacid;6-((Morpholin-4-ylcarbonyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)hexanoicacid;N-Butyl-4-(hydroxymethyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}piperidine-1-carboxamide;N-Butyl-N′-(6-hydroxyhexyl)-N′-methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea;Ethyl7-({[ethyl(4-hydroxybutyl)amino]carbonyl}{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)heptanoate;N-(4-Cyanobutyl)-N′-ethyl-N′-(4-hydroxybutyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea;N-(4-Cyanobutyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carboxamide;7-({[Ethyl(4-hydroxybutyl)amino]carbonyl}{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]amino)heptanoicacid;7-((Morpholin4-ylcarbonyl){4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)heptanoicacid;N-[4-(1H-Tetraazol-5-yl)butyl]-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carboxamide;N-Butyl-N′-(2,3-dihydroxypropyl)-N′-methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea;N-Butyl-N′-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-N′-methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}urea;Methyl4-({[ethyl(4-hydroxybutyl)amino]carbonyl}{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)butanoate;4-({[Ethyl(4-hydroxybutyl)amino]carbonyl}{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)butanoicacid;N-(Pyridin-2-ylmethyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carboxamide;N-(3-Fluoropropyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carboxamide;N-(2-Methylprop-2-enyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl]phenyl}morpholine-4-carboxamide;N-[(4-Cyanophenyl)methyl]-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carboxamide;N-[4-(3-Methyl-1,2,4-oxadiazol-5-yl)butyl]-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carboxamide;4-Chloro-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}benzenesulfonamide;4-Chloro-N-[4-(1H-tetraazol-5-yl)butyl]-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}benzenesulfonamide;4-Fluoro-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}benzenesulfonamide;4-Chloro-N-(4-cyanobutyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}benzenesulfonamide;N-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}piperidine-1-sulfonamide;N-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}benzenesulfonamide;N-Methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}methanesulfonamide;N-Propyl-N′-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}sulfamide;N,N′-Dicyclohexyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}imidodisulfuric diamide;N-Methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}benzenesulfonamide;4-Chloro-N-ethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}benzenesulfonamide;N-Methyl-N′-(3-methylbutyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}sulfamide;N,N-Bis(2-methylpropyl)-N′-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}sulfamide;N,N-Diethyl-N′-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}sulfamide;N-(3-Methylbutyl)-N′-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}sulfamide;N-{[(1,1-Dimethylethyl)oxy]carbonyl}-N′-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}sulfamide;N-Pentyl-N′-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}sulfamide;N,N′-Bis{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}sulfamide;N,N-Bis(3-methylbutyl)-N′-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}sulfamide;N,N-Bis(2-methylpropyl)-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide;N-(Cyclopropylmethyl)-N-propyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide;N-(2-Cyanoethyl)-N-ethyl4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl]benzamide;N-Ethyl-N-[2-(methyloxy)ethyl]4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide;1,1,1,3,3,3-Hexafluoro-2-[4-(pyrrolidin-1-ylcarbonyl)phenyl]propan-2-ol;1,1,1,3,3,3-Hexafluoro-2-[4-(piperidin-1-ylcarbonyl)phenyl]propan-2-ol;andN-Methyl-N-(phenylmethyl)-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide.6. A method according to claim 4 comprising the administration of acomposition containing a compound selected from the group consisting of:3-{[(1-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-2-yl)thio]methyl}benzonitrile;3-{[(1-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-2-yl)sulfonyl]methyl}benzonitrile;2-(2-Methylpropyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carbaldehyde;2-(1-Methylethyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carbaldehyde; Ethyl(2E)-3-(2-(1-methylpropyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-5-yl)prop-2-enoate;Methyl(2E)-3-(2-(1-methylpropyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-5-yl)prop-2-enoate;Methyl3-(2-(1-methylpropyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-5-yl)propanoate;1,1,1,3,3,3-Hexafluoro-2-{4-[5-(1-hydroxyethyl)-2-(1-methylpropyl)-1H-imidazol-1-yl]phenyl}propan-2-ol;1-(2-(1-Methylpropyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-5-yl)butan-1-ol;2-Methyl-1-(2-(1-methylpropyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-5-yl)propan-1-ol;1,1,1,3,3,3-Hexafluoro-2-{4-[5-[(4-fluorophenyl)(hydroxy)methyl]-2-(1-methylpropyl)-1H-imidazol-1-yl]phenyl}propan-2-ol;(2E)-3-(2-(1-Methylethyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-5-yl)prop-2-enenitrile;(2Z)-3-(2-(1-Methylethyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-5-yl)prop-2-enenitrile;5-{[(2-(1-Methylethyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-5-yl)methyl]oxy}pentanenitrile;6-{[(2-(1-Methylethyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-5-yl)methyl]oxy}hexanenitrile;2-(1-Methylethyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carbaldehyde O-(1,1-dimethylethyl)oxime;2-(1-Methylethyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carbaldehydeoxime;1,1,1,3,3,3-Hexafluoro-2-{4-[2-(1-methylethyl)-5-({[5-(1H-tetraazol-5-yl)pentyl]oxy}methyl)-1H-imidazol-1-yl]phenyl}propan-2-ol;2-(1-Methylethyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carbeldehydeO-methyloxime;2-(1-Methylethyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carbaldehydeO-ethyloxime;2-(1-Methylethyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carbaldehydeO-ethyloxime; Methyl(2E)-3-(2-(1-methylethyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-5-yl)prop-2-enoate;Ethyl(2E)-2-methyl-3-(2-(1-methylethyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-5-yl)prop-2-enoate;Methyl3-(2-(1-methylethyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}1H-imidazol-5-yl)propanoate;N-Butyl-N′-(3,5-dimethylisoxazol-4-yl)-N-[(2-(1-methylethyl)-1-{4-[2,2,2trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-5yl)methyl]urea;1,1,1,3,3,3-Hexafluoro-2-{4-[2-(1-methylethyl)-5-({[4-(1H-tetraazol-5-yl)butyl]oxy}methyl)-1H-imidazol-1-yl]phenyl}propan-2-ol;2-(1-Methylethyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carbaldehydeO-methyloxime; Ethyl2-methyl-3-(2-(1-methylethyl)-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-5-yl)propanoate;2-Pyridin-4-yl-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carbaldehyde;1,1,1,3,3,3-Hexafluoro-2-{4-[5-(hydroxymethyl)-2-pyridin4-yl-1H-imidazol-1-yl]phenyl}propan-2-ol;Ethyl 2-pyridin-4-yl-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-4-carboxylate;4-Iodo-N-(3-pyridin-4-yl-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-pyrazol-5-yl)benzenesulfonamide;1,1,1,3,3,3-Hexafluoro-2-[4-(3-methyl-5-pyridin-4-yl-1H-pyrazol-1-yl)phenyl]propan-2-ol;2-Methyl-N-(3-pyridin-4-yl-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-pyrazol-5-yl)propanamide;2-[4-(3,5-Dipyridin-2-yl-1H-pyrazol-1-yl)phenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol;1,1,1,3,3,3-Hexafluoro-2-[4-(3-methyl-5-pyridin-3-yl-1H-pyrazol-1-yl)phenyl]propan-2-ol;N-(3-Pyridin-4-yl-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-pyrazol-5-yl)isonicotinamide;1-(3-Pyridin-4-yl-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-pyrazol-5-yl)pyrrolidine-2,5-dione;4-Oxo-4-[(3-pyridin-4-yl-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-pyrazol-5-yl)amino]butanoicacid; Ethyl3-(5-methyl-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-pyrazol-3-yl)propanate;and Ethyl3-(3-methyl-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-pyrazol-5-yl)propanoate.7. A method for the preparation of the compound of the formulae XIIIaand XIIIb which comprises treating aniline derivative of the formula IIIwith R₇CN in the presence of a Lewis acid at elevated temperature or astrong base, yielding compound of the formula XI and treating saidcompound XI with α-haloketone or α-haloaldehyde in a solvent


8. A process according to claim 7 wherein said Lewis acid is aluminumchloride and said strong base is lithium hexamethyldisilyl amide.
 9. Aprocess according to claim 7 wherein said elevated temperature is about160° C.
 10. A method for shifting fatty acid metabolism to carbohydratemetabolism in a patient by increasing malonyl-CoA concnetration whichcomprises the administration of therapeutically effective amount of acomposition as defined in claim
 1. 11. A method for treating diseasesassociated with fatty acid and glucose metabolism mediated bymalonyl-CoA decarboxylase in a patient which comprises theadministration of therapeutically effective amount of a composition asdefined in claim
 1. 12. A method according to claim 11 wherein saiddisease is a cardiovascular disease.
 13. A method according to claim 12wherein said cardiovascular disease is congestive heart failure.
 14. Amethod according to claim 12 wherein said cardiovascular disease is anischemic cardiovascular disease.
 15. A method according to claim 14wherein said ischemic cardiovascular disease is angina pectoris.
 16. Amethod according to claim 11 wherein said disease is diabetes.
 17. Amethod according to claim 11 wherein said disease is obesity.
 18. Amethod according to claim 11 wherein said disease is acidosis.
 19. Amethod according to claim 11 wherein said disease is cancer.